Melanocortins are known to have a broad array of physiological actions (Nakanishi, et al. Nature (1979) 278:423-427). Aside from their well known effects on adrenal cortical functions and on melanocytes, melanocortins have been shown to affect behavior, learning, memory, control of the cardiovascular system, analgesia, thermoregulation, and the release of other neurohumoral agents including prolactin, luetinizing hormone, and biogenic amines (De Weid et al. Methods Achiev. Exp. Pathol. (1991) 15:167-199; De Weid et al. Physiol Rev. (1982) 62:977-1059; Gruber, K. A. et al. Am. J Physiol. (1989) 257:R681-R694; Murphy et al. Science (1980) 210:1247-1249; Murphy et al. Science (1983) 221:192-193; Ellerkmann, E. et al. Endocrinol. (1992) 130:133-138; Versteeg, D. H. G. et al. Life Sci. (1986) 835-840). Peripherally, melanocortins have been identified to have immunomodulatory and neurotrophic properties, and to be involved in events surrounding partition (Cannon, J. G. et al. J. Immunol. (1986) 137:2232-2236; Gispen, W. H. Trends Pharm. Sci. (1992) 11:221-222; Wilson, J. F. Clin. Endocrinol. (1982) 17:233-242; Clark, D. et al. Nature (1978) 273:163-164; Silman, R. E. et al. Nature (1976) 260:716-718). Furthermore, melanocortins are present in a myriad of normal human tissues including the brain, ovary, lung, thyroid, liver, colon, small intestine and pancreas (Tatro, J. B. et al. Endocrinol. (1987) 121:1900-1907; Mountjoy, K. G. et al. Science (1992) 257:1248-1251; Chhajlani, V. et al., FEBS Lett. (1992) 309:417-420; Gantz, L. et al., J. Biol. Chem. (1993)268:8246-8250; Gantz, L. et al, J. Biol. Chem. (1993)268:15174-15179).
Recent studies have described an unexpected diversity of subtypes of receptors for the melanocortin peptides and determined that they belong to the superfamily of seven transmembrane G-protein linked cell surface receptors (Mountjoy, K. G. et al. Science (1992), supra; Chhajlani, V. et al., FEBS Lett. (1992), supra). Five melanocortin receptor subtypes have been cloned. The melanocortin-1 (MC1) receptor is found in melanoma cells, where it has a role in mediating pigmentation. The melanocortin-2 receptor (MC2-R or ACTH receptor) is found in the adrenal glands where it mediates the effects of ACTH (adrenocorticotrophic hormone). The melanocortin-3 receptor (MC3-R) is primarily found in the central nervous system (CNS) (Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250), but its physiological function is still unknown. The melanocortin-4 receptor (MC4-R) has been found in the brain, where it is widely distributed in several areas, including the cortex, thalamus, hypothalamus, brain stem, and spinal cord (Gantz, L. et al. J. Biol. Chem. (1993) 268:15174-15179; Mountjoy, K. G. et al. Mol. Endocrinol. (1994) 8:1298-1308). MC4-R has recently been related to weight homeostasis. MC4-R xe2x80x9cknock outxe2x80x9d mice have been shown to develop obesity (Huszar et al. Cell (1997) 88:131-141). The feeding behavior leading to the obesity can be inhibited by injection of MSH peptides (Vergoni et al. Neuropeptides (1986) 7:153-158; Vergoni et al. Eur. J. Pharmacol (1990) 179:347-355; Fan et al. Nature (1997) 385:165-168). The melanocortin-5 receptor (MC5-R) has a wide peripheral distribution and is believed to participate in the regulation of the exocrine gland function (Chen et al. Cell (1997) 91:789-798).
In one aspect, the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal. The method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. The MC4-R binding compound is of the formula (I):
Bxe2x80x94Zxe2x80x94Exe2x80x83xe2x80x83(I)
wherein B is an anchor moiety, Z is a central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
In a further embodiment, the MC4-R binding compound is of the formula (II):
Bxe2x80x94Axe2x80x94Exe2x80x83xe2x80x83(II)
wherein B is an anchor moiety, A is cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
In another embodiment, the invention pertains to another method for treating an MC4-R associated state in a mammal, by administering to a mammal an effective amount of a MC4-R binding compound of formula (III):
xe2x80x83Bxe2x80x94L1xe2x80x94Axe2x80x94L2xe2x80x94Exe2x80x83xe2x80x83(III)
wherein B is an anchor moiety, L1 and L2 are linking moieties, A is a cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
The invention also pertains to treating MC4-R associated states with an MC4-R binding compound of formula III, wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; L1 is a covalent bond, C1-C10 branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; and A is a substituted or unsubstituted phenyl, heteroaryl, cycloalkyl, or biaryl, and pharmaceutically acceptable salts thereof.
In another embodiment, the invention pertains to a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. In this embodiment, the compound is of the formula (IV): 
wherein B is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; A is aryl, heteroaryl, biaryl, cycloalkyl, heterocyclic, or cycloalkenyl; L1 and L2 are selected from the group consisting of a covalent bond, C1-C6 branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH2, CHR1, CR1R2, or H; t is CH, CH2, CHR3, CR3R4, or H; s is CHR5, CR5, CR5R6 or absent (e.g., leaving a non cyclic diamine); R is H, substituted or unsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally be linked to A, B, L1, or L2; R1, R2, R3, R4, R5, and R6 are each substituted or unsubstituted alkyl alkenyl, halogen, thiol, thioether, thioalkyl, or alkoxy, and may optionally be linked to form a carbocyclic or heterocyclic ring. Pharmaceutically acceptable salts of the MC4-R binding compound are also included.
The invention also pertains to methods for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound of the formula (V): 
wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; L1 is a covalent bond, C1-C10 branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; Π is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, cycloalkyl, or aryl; L3 is a covalent bond, C1-C6 branched, unbranched or cyclic alkyl, wherein one, two or three of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl; and xcex9 is heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and xcex is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
In yet another embodiment, the invention also pertains to a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, wherein the compound is an MC4-R antagonist, and is of the formula (VI): 
wherein
P1, P2, P3, and P4 are optionally substituted carbon, sulfur, or nitrogen, and wherein one of P1, P2, P3 and P4 may represent a covalent bond; Z1, Z2, Z3, Z4, and Z5 are optionally substituted carbon or nitrogen; L1 is a covalent bond, C1-C10 branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
In another embodiment, the MC4-R binding compound is of formula (VII): 
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; and
P1, P2, P3, P4, and P5 are CH, N or substituted carbon.
In another embodiment, the MC4-R binding compound is of formula (VIII): 
wherein
Z1, Z2, Z3, Z4, and Z5 are CH, N, or substituted carbon; and
P1, P2, P3, P4, and P5 are CH, N or substituted carbon.
The invention also pertains to MC4-R binding compound of the formula (IX): 
wherein:
P2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, Cxe2x80x94CN, Cxe2x80x94OH, CI, or a covalent bond;
P3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, Cxe2x80x94CN, Cxe2x80x94OH, or CI;
P4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, Cxe2x80x94CN, Cxe2x80x94OH, CI, or a sulfur atom;
G1 and G2 are each independently CH2, S, or O;
r is a covalent bond or CH2;
t is CH2, CHR3, or CR3R4;
s is CH2, CHR5 or CR5R6;
R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl;
Z1 is CH, or covalently linked to Z2 to form a naphthyl ring;
Z2 is CH, Cxe2x80x94(Cxe2x89xa1CH), CCl, CBr, CI, CF, or covalently linked to Z1 to form a naphthyl ring;
Z1 is CH, C-alkoxy or Cxe2x80x94OMe;
R3, R4, R5, and R6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.
The invention also features a pharmaceutical composition for the treatment of a MC4-R associated state in a mammal. The pharmaceutical compositions contain a pharmaceutically acceptable carrier and a MC4-R binding compound. The compounds are described herein in the context of the description of the method but it should be understood that the invention further pertains to pharmaceutical compositions containing the compounds and the compounds per se. For example, pharmaceutical compositions of the invention include a pharmaceutically acceptable carrier and an effective amount of at least one MC4-R binding compound of the formula (I):
Bxe2x80x94Zxe2x80x94Exe2x80x83xe2x80x83(I)
wherein B is an anchor moiety, Z is an central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.